NRSA F32 APPLICATION ?Effects of Toluene On The Adolescent and Young Adult Mesocorticolimbic Pathway. PI: Wesley N. Wayman, Ph.D. Sponsor: John J. Woodward Ph.D. Abstract This NRSA application will support post-doctoral training in an individualized, integrated program involving physiology, neuroanatomy, morphology, and neurocircuitry of substance abuse. Many common household products such as paints, paint thinners, and glues, contain volatile organic substances (e.g. toluene) that are inhaled to produce mind-altering effects. Commonly referred to as inhalants, studies by the National Institute on Drug Abuse indicate that approximately 21.7 million Americans aged 12 and older have used inhalants at least once in their lives and are often one of the first and easiest options for abuse among adolescents and young adults trying drugs (NSDUH, 2013). Inhalants, like classical drugs of abuse, possess positive-reinforcing properties in rodent behavioral studies (Gerasimov et al., 2003, Blokhina et al., 2004, Lee et al., 2006) and are capable of modifying the reward circuitry, including key regions such as the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and ventral tegmental area (VTA) (Beckley and Woodward, 2011, Beckley et al., 2013, Beckley et al., 2015). Studies in this proposal will extend these findings by examining the effect of in vivo toluene exposure on markers of mPFC neuroplasticity/neurophysiology in adolescent/young adult rats. Specific Aim 1 will use whole-cell patch-clamp electrophysiology and dendritic spine analysis to determine whether toluene vapor exposure induces acute physiological and morphological alterations of mPFC pyramidal neurons. A novel in vivo fiber photometry approach coupled with the genetically encoded calcium sensor GCaMP6 will validate changes in mPFC activity in awake freely moving animals. Specific Aim 2 will test whether toluene-induced alterations in mPFC neuron excitability can be attenuated by modulating neuronal firing with DREADDs and will determine whether such modulation of neuronal firing attenuates toluene-induced CPP. Understanding the effects of toluene in adolescent and young adult rats will help elucidate the neural bases of toluene's abuse potential while expanding my technical abilities and advancing my career objective of becoming an independent academic neuroscientist.